Because their aberrant activity is implicated in human cancer, ErbB receptor tyrosine kinases (ErbB1/EGFR, ErbB2/HER2/neu, ErbBS, and ErbB4) have become targets of cancer therapeutics designed to interfere with their signaling by inhibiting ligand binding, receptor dimerization, and kinase activity. While the first generation of these drugs shows promise, we are just beginning to appreciate the details of how they work (e.g., alterations to receptor trafficking) and in which contexts (i.e., ErbB expression profiles) particular agents (or combinations thereof) may be most effective. To enhance this understanding, we propose an experimental and modeling approach. Using cell lines with known ErbB profiles, we will measure the ability of various inhibitors to interrupt ErbB-mediated signaling and the effects of those inhibitors on ErbB trafficking (internalization, recycling, degradation). Using measured parameters, we will develop an ErbB trafficking and signaling model to enable prediction of which therapeutics will be most effective for a given ErbB profile. Ultimately, this work portends enhanced understanding of how to better design ErbB-targeted agents and how to best treat individuals with available therapies based on their ErbB expression.